Citalopram is a selective serotonin reuptake inhibitor which has successfully been marketed as an antidepressant drug for some years. It has the following structure: and it may be prepared by the process described in U.S. Pat. No. 4,650,884 according to which 5-cyanophthalide is subjected to two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively, and the resulting dicarbinol compound is subjected to a ring closure reaction by dehydration. The 5-cyanophthalide may in its turn be obtained by reaction of 5-carboxyphthalide with a dehydrating agent and a sulfonamide of the formula H2N—SO2—R wherein R is NH2, alkyloxy, optionally substituted phenyloxy, or substituted phenyl in order to obtain 5-cyanophthalide, cf. our co-pending Danish patent application No. PA199801718.
5-Carboxyphthalide has been described as a useful intermediate in the polymer and paint industry. However, no reliable commercial source is available at present. A known process comprises catalytic hydrogenation of trimellithic acid (DE-A1 2630927). This process provides a mixture of the 5- and 6-carboxyphthalides and, accordingly, it requires elaborate and costly purification. According to J. Org. Chem. 1970, 35, p. 1695-1696, 5-carboxyphthalide is synthesised by reaction of terephthialic acid with trioxanie in liquid SO3. During this process, trioxane sublimates and precipitates thereby obstructing the equipment.
Though a number of other methods failed, it has now been found that 5-carboxyphthalide may be prepared from terephthalic acid in high yields by a convenient, cost-effective procedure.